Clinical-stage drug developer Terns Pharmaceuticals on Tuesday announced promising data from its Phase I clinical study evaluating its small molecule allosteric BCR-ABL inhibitor drug candidate TERN-701 in patients with relapsed/refractory chronic myeloid leukemia (CML). The CARDINAL trial’s data from 15 patients exhibited both safety and efficacy at all four dosing levels of patients with relapsed/refractory CML with or without BCR-ABL resistance mutations, who were previously treated with at least one 2G tyrosine kinase inhibitor (TKI).
“These exciting early data from our Phase I dose escalation cohorts clearly show TERN-701 has compelling clinical activity with a highly encouraging cumulative MMR rate of 50% at three months,” said Emil Kuriakose, MD, chief medical officer of Terns. “At the first two dose levels, we see clinically meaningful molecular and hematologic responses in patients with high baseline BCR-ABL transcript levels who had poor responses on prior 2G TKIs, 3G TKIs including ponatinib, as well as asciminib.”
For more than 20 years, since the approval of imatinib (Gleevec) in 2001, chronic myeloid leukemia (CML) has been treated with TKIs—treatments that don’t eradicate all leukemic cells, but nonetheless lower the total population of these cells such that people diagnosed with CML can expect a normal lifespan. Yet, while TKIs can preserve life expectancy, imatinib, and other second- and third-generation TKIs are associated with a range of side effects due to off-target effects.
TERN-701 is from a new class of CML drugs called allosteric BCR-ABL inhibitors, which instead of binding to the ATP-binding site, bind to a non-active site on the BCR-ABL protein to indirectly influence its activity by changing the shape of the protein. The first drug from this class asciminib (Scemblix) was approved by the FDA in October of 2021 for patients previously treated with at least two TKIs. Earlier this year, the FDA granted asciminib priority review designation for the treatment of newly diagnosed CML patients in the chronic phase.
Safety data for the allosteric inhibitor from the first portion of the two-tiered study, which showed no dose-limiting toxicities from three different dosing levels, including no adverse event discontinuations at levels that achieve effective dose concentrations, have Terns executive believing they have what is a “best-in-class” allosteric inhibitor for CML.
“Pre-clinically, we have shown that TERN-701 has potency equal to or greater than asciminib across multiple mutational variants. We’ve also confirmed clinically that TERN-701 can be dosed once daily without food, a key differentiator that is particularly important in a disease where patients are on therapy for life,” said Terns CEO, Amy Burroughs, in a conference call announcing the results. “As we progress in clinical trials, we have a scientific hypothesis that TERN-701 has the potential to demonstrate improved efficacy, safety, and ease of use. This is supported by our own preclinical potency data, as well as learning from an asciminib development and long-term clinical data, which together suggests that 701 through better dose optimization, could not only potentially outperform on efficacy while maintaining good safety, but also allow for unified dosing across all CML patients.”
As of the October 28, 2024 cutoff date, the trial had enrolled 15 patients across dosing levels of 160mg, 320mg, and 400mg of TERN-701 which was given once daily. Enrolled patients had been heavily pre-dosed with TKIs with a median of four TKIs per patients with 80 having been treated with three or more TKIs.
At the cutoff date, a dozen patients were evaluable to demonstrate efficacy defined as having baseline BCR-ABL transcript and at least two post-baseline BCR-ABL transcript levels. Efficacy data was derived from patients in the 160mg and 320mg dosing levels.
Efficacy data showed:
- Seven of eight patients with baseline transcript > 1% had decreases in BCR-ABL on treatment, with seven ongoing as of data cutoff;
- Cumulative MMR rate of 50% (5/10) in non-T315i mutation patients with three or more months of treatment and/or MMR or better at baseline; and
- 100% (4/4) of patients with MMR or better at baseline have maintained their response and remain on treatment.
Key safety data include:
- No dose limiting toxicities through 400mg dose level;
- No adverse event (AE)-related treatment discontinuations or dose reductions;
- No Grade 3 or higher treatment-related AEs; and
- No treatment related serious AEs.
While the first part (dose escalation) of the CARDINAL trial had a primary endpoint of safety and tolerability and a secondary endpoint on pharmacokinetics and efficacy, part two (dose expansion) flips these around with drug efficacy the first endpoint and safety the second endpoint.
As of yesterday’s data release, the trial now enrolls 19 patients and will look to have 20 patients enrolled at each of two, as yet undetermined, dosing levels. According to Kuriakose, part two of the study is expected to begin in the first half of 2025.
